Method of producing anti-adrenal activity with diarylalkylamines



"United States Patent Int. (:1. A61k 27/00 US. Cl. 424-330 4 Claims ABSTRACT OF THE DISCLOSURE Diphenyl alkyl amines are disclosed having adrenocortical inhibitory properties. The diphenyl propylamines show selected suppression of aldosterone. These compounds are synthesized by methods known to the art.

This is a continuation-in-part of my copending application Ser. No. 400,551 filed Sept. 30, 1964, now abandoned.

This invention relates to pharmaceutical preparations having adrenocortical inhibitory properties and to a method of producing anti-adrenal activity in animals.

More specifically, the pharmaceutical preparations and method of this invention can be used whenever it is desired to suppress adrenal glandular function, thereby inhibiting the synthesis of adrenal steroids in order to, for example, reduce hypertension, edema or hyperglycemia.

The pharmaceutical compositions of this invention are unique in that they selectively block the production of adrenal steroids while being free of estrogenic activity. Anti-adrenal activity has not been disclosed for compounds of the chemical class described hereinafter.

Further, the active ingredient of these compositions is rapidly absorbed, particularly from the gastro-intestinal tract after oral administration, with remarkably low toxicity within the close ranges set forth hereinafter.

The compositions of this invention are in dosage unit form and comprise a nontoxic pharmaceutical carrier and a substituted aliphatic amine which has the following structural formula:

FORMULA I RI! Y (on2 1-Y' I i in which:

Y and Y are phenyl, naphthyl, cycloalkyl from to 8 carbon atoms, pyridyl, or derivatives of phenyl, naph thyl, or pyridyl having substituents selected from the group consisting of amino, alkylamino having up to 4 carbon atoms, dialkylamino having up to 8 carbon atoms, benzylamino, acylamino having up to 3 carbon atoms, halogen, such as chloro, tr'ifluoromethyl, hydroxy, mercapto, lower alkyl having up to 3 carbon atoms, lower alkoxy having up to 3 carbon atoms, lower alkylthio having up to 3 carbon atoms, lower alkylsulfinyl having up to 3 carbon atoms, lower alkylsulfonyl having up to 3 carbon atoms, lower acyl having up to 3 carbon atoms, trifluoromethylthio, trifluoromethylsulfonyl or trifluoromethoxy;

X is amino or ANRR, wherein A is an alkylene linkage of from 1 to 4 carbon atoms which may be straight or branched, and R and R are lower alkyl having up to 3 carbon atoms, lower acyl having up to 3 carbon atoms, or hydrogen;

R is hydrogen, alkyl to 7 carbon atoms, phenyl or benzyl; and

n is an integer one or zero.

Advantageously, the substituted aliphatic amines are those represented by the above structure in which n is zero, Y and Y are phenyl, R is hydrogen or alkyl to 7 carbon atoms, and X is ANRR, with A, R and R as defined above, and depicted by Formula II below:

FORMULA II in which Z and Z represent amino, alkylamino having up to 4 carbon atoms, dialkylamino having up to 8 carbon atoms, lower alkyl having up to 3 carbon atoms, hydroxy, lower alkoxy having up to 3 carbon atoms, mercapto, lower alkylthio having up to 3 carbon atoms, lower alkylsulfinyl having up to 3 carbon atoms, lower alkylsulfonyl having up to 3 carbon atoms, lower acyl having up to 3 carbon atoms, bromine, chlorine, fluorine, trifluoromethyl, trifluoromethylthio, trifluoromethylsulfonyl, tri fluoromethoxy or hydrogen.

The compounds of Formula II are advantageous as compounds which inhibit the synthesis of important adrenal corticosteroids. For example, among these are:

2,2-diphenylethylamine; Z-(p-aminophenyl)-2-phenethylamine; 2-phenyl-2-(p-trifluoromethylphenyl) ethylamine; 2-phenyl-2-p-methylthiophenylethylamine; 2-p-methylsulfonylphenyl-Z-phenylethylamine; and 2- (p-aminophenyl) -2-phenylpropylamine.

Certain other compounds of Formula II are preferred, where selective suppression of the particularly important corticosteroid, aldosterone, is desired. Exemplary of these are:

3 ,3-diphenylpropylamine;

3- (p-methoxyphenyl -3-phenylpropylamine; 3-phenyl-3-p-trifluoromethylphenylpropylamine; 3-phenyl-3- (m-tolyl -propylamine; and

3- (p-methylthiophenyl -3-phenylpropylamine.

Most advantageously, the compositions of this inven tion in dosage unit form comprise a nontoxic pharmaceutical carrier and one of the above-described anti-adrenal compounds, or one of its acceptable acid addition salts.

It will be readily apparent to one skilled in this art that the substituted aliphatic amine compounds of this invention may have asymmetric carbon atoms, forming optically active dand l-compounds. The connotation of the general formulas presented herein is intended to include the separated a. or 1 optical isomers, as well as racemic mixtures of these isomers.

If desired, the isomers may be separated for individual use by resolution methods known to the art, such as frac' tional crystallization of the l-tartrate salts of the diamines. Alternatively, a synthesis starting with an optically active side chain may yield the desired optical isomer.

Basically substituted diamines as illustrated in Formula I (n=0) and present in these novel compositions are prepared by reduction of the arylcylanomethylenequinone oximes to give p-aminoarylarylethylamines, as described by R. B. Davis et al. in the Journal of Chemical and Engineering Data, 8, Number 4, October 1963, page 578. A wide variety of chemical methods can be employed to reduce these oximes to the monoand di-amines. Treating of these amines with alkylating agents and acylating agents leads to the aryl substituted amines, or the amino hydrogen substituted amines of this invention.

The benzyl congeners, i.e., (n=1) of the diphenyl ethyl amine compounds just described are prepared in similar manner, starting with the appropriate substituted benzaldehyde and a suitable phenyl acetonitn'le to form the corresponding 2,3-diphenyl acrylonitrile. This intermediate is vigorously reduced using hydrogen and Raney nickel in methanol, to yield the desired substituted l-aryl- 2-arylpropylamine.

The pyridyl congeners of the diarylalkylamine compounds are prepared by alkylating suitably substituted arylacetonitriles with halopyridines in the presence of a strong base such as sodamide or sodium hydride.

The cycloalkyl congeners of the diaryl alkylamino compounds are prepared from appropriately substituted phenylacylnitrile by treatment with a cycloalkanone, such as cyclohexanine. The resulting intermediate, a cycloalkylidene, substituted phenyl acylnitrile, is catalytically reduced, yielding the corresponding substituted phenylcycloalkyl alkylamine.

Generally, diarylalkylamines of Formula I may be obtained from the corresponding diarylalkanoic acid amides by reduction with lithium aluminum hydride. Exemplary syntheses are set forth in the examples.

A nontoxic pharmaceutically acceptable organic or inorganic acid addition salt of the base may be used instead of the base. Preferably, the hydrochloride salt is used. However, other salts such as those derived from sulfuric, nitric, phosphoric, citric, acetic, lactic, mandelic, salicylic, phthalic, fumaric, maleic, tartaric, hydrobromic, benzoic and like nontoxic acids may be used. The salts are best prepared by reacting the free base with a stoichiometric amount of the desired organic or inorganic acid in a suitable solvent, such as ethyl acetate-ether solution, ethanol, acetone, water or various combinations of solvents. In addition to the acid addition salts, the quaternary ammonium salts may be employed.

The pharmaceutical carrier employed may be, for example, either a solid or liquid. Exemplary of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Exemplary of liquid carriers are syrup, peanut oil, olive oil, water and the like. Similarly the carrier or diluent include any time delay material well known to the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax.

A wide variety of pharmaceutical forms can be employed. Thus, if a solid carrier is used the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge. The amount of solid carrier will vary widely but preferably will be from about 25 mg. to about 1 g. If a liquid carrier is used, the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, ampul or liquid suspension.

The method in accordance with this invention comprises administering internally to an animal organism a compound as represented by the above formula, or a nontoxic addition salt thereof, usually combined with a pharmaceutical carrier, for example, any of the above compositions in an amount sufficient to produce anti-adrenal activity. The active medicament preferably will be, typically per unit of hydrochloride salt, in an amount of from about 5 mg. to about 800 mg. and advantageously from about 100 mg. to about 500 mg. As a free base, the unit dosage will contain from about 20 mg. to about 600 mg. The administration may be parenterally or orally, the latter being the preferable route of administration. Advantageously equal doses will be administered two to twelve times daily. Preferably the daily dosage regimen will be from 0.05 g. to about 16 g., and most advantageously from about 0.1 g. to about 4.0 g. of active medic ament in pharmaceutical forms. At the higher daily dosage, two or more capsules or tablets may be taken at each administration to attain the intended dosage level. When the administration described above is carried out, anti-adrenal activity is effectively achieved.

In certain veterinary practices, the preparations can also be given per se, or as an additive to the feed or drinking matter of animals.

These preparations are made following the conventional techniques of the pharmaceutical chemist involving mixing, granulating and compressing when necessary or variously mixing and dissolving the ingredients as appropriate to the desired end product. I

The following examples are not limiting but are illustrative of pharmaceutical preparations of this invention.

EXAMPLE 1 Preparation of 2-phenyl-2- (p-aminophenyl)-ethyl amine A suitable reaction vessel is charged with 111 g. of phenylcyanomethylene quinone oxime, a solution of 20 g. of potassium hydroxide (assay in 400 ml. of methanol, two teaspoons of Raney nickel catalyst No. 28, and hydrogen under an initial pressure of about 1180 lbs. per square inch. The vessel is rocked and slowly heated to about 80 C., maintaining that temperature for about three hours. During the heating process, additional hydrogen is charged to the vessel so as to maintain a hydrogen pressure of about 800 lbs. per square inch as a minimum. There is then isolated 81 g. of Z-phenyI-Z-(p-aminophenyl)-ethyl amine (75% yield), M.P. 9910l C.

When the above procedure is repeated, omitting, however, the potassium hydroxide and the phenylcyanomethylene quinone oxime, and using instead the potassium salt of phenylcyanomethylene quinone oxime, the same product is obtained in good condition and in good yield.

EXAMPLE 2 Preparation of 2-phenyl-2-(3-methoxy-4-aminophenyl)- ethyl amine To a reaction vessel containing 60 g. of 2-methoxy-4- (phenylcyanomethylene)-cyclohexa-2,5 diene-l-one oxime, 500 ml. of methanol and 60 .g. of amalgamated zinc dust, is added in increments over one hour with stirring and cooling, 160 ml. of acetic acid. The reaction mixture is then cautiously heated to reflux, with refluxing and stirring being maintained for five hours. During this period, an additional 20 g. of amalgamated zinc dust and 40 ml. of water are added in increments. The reaction mixture is cooled, filtered and 1500 ml. of water are added with stirring to the filtrate. The phenyl-(3-methoxy 4' aminophenyl)-acetonitrile which settles to the bottom of the mixture is removed, Washed with water and after drying, melts at about 53 C. yield).

An autoclave is charged with 10 g. of phenyl-(3'- methoxy-4'-aminophenyl)-acetonitrile, 100 ml. of methanol, 2 g. of a slurry of Raney nickel in water, 20 g. of ammonia and hydrogen under pressure of 1000 lbs. per square inch. The reaction vessel is heated with shaking to C., maintaining that temperature for two hours. After cooling and releasing the pressure, the contents are filtered. Upon removing the methanol and ammonia, and purifying the compound, there is isolated 2-phenyl-2-(3- rnethoxy-4'-aminophenyl)-ethyl amine. The dihydrochloride, M.P. 213-215 C., is formed by dissolving the diamine in ether and treating the solution with an excess of dry hydrogen chloride.

EXAMPLE 3 Preparation of N,N'-bisacetyl-2-(4-aminophenyl)-2- phenyl-ethylamine A suitable reaction vessel is charged with 0.10 mole of 2-phenyl-2-(p-aminophenyl)-ethylamine, the preparation of which has been described in Example 1, 0.30 mole of acetic anhydride, 20 ml. of acetic acid, and approximately 0.1 g. of zinc dust which are heated at reflux. The reaction mixture is then poured with stirring into another vessel containing about 250 g. of ice and 250 ml. of Water. After standing for about four hours, the product is col lected, washed with water and air dried. There is then isolated about 0.8 mole of N,N-bisacetyl-2-(4'-aminophenyl)-2-phenylethylamine (79% yield), M.P. 9091 C.

EXAMPLE 4 Preparation of 2- (p-chlorophenyl) -2-phenylethylamine dihydrochloride A mixture of 65 g. of 4-oxo-a-p-chlorophenyl-2,5-cyclohexadiene-A, ot-acetonitrile oxime [R. B. Davis and J. D. Benigni, Journal of Chemical and Engineering Data, 8, 578 (1963)], 430 ml. of absolute methanol, and one level teaspoon of Raney nickel is added to a 1 liter bomb. Partial reduction is effected at room temperature and 300 p.s.i. of hydrogen. When this reduction is completed, the bomb is vented and 30 ml. of liquid ammonia is added. The reduction is completed at 55 C. and 1000 p.s.i. of hydrogen. The bomb is opened and the contents are filtered. The filter cake is washed withmethanol and the combined filtrates are evaporated to produce an oil. The oil is dissolved in ethyl acetate and saturated with hydrogens chloride gas. The resulting solid dihydrochloride is filtered and dissolved in water. The aqueous solution is extracted several times with ether. The aqueous layer is made alkaline and extracted with ethyl acetate. The combined organic phases are washed with water, dried over magnesium sulfate and concentrated. The concentrate is saturated with hydrogen chloride; the solid formed is filtered and suspended in hot l-butanol. The butanol is cooled and the pale yellow solid is filtered and recrystallized from methanol-ethyl acetate (yield 22 g.), M.P. 293-295" C. dec.

EXAMPLE 5 Preparation of 2-(p-methylaminophenyl)-2- phenylethylamine dihydrochloride To a solution of g. (0.048 mole) of (p-aminophenyl)-phenylacetonitrile (prepared by the zinc amalgam reduction of 4-OXO-0L-Ph6ny1-2,5-CyClOh6XadleIl6-A',0tacetonitrile oxime as described in Example 4) in 125 ml. of ether is added 25 ml. of a saturated aqueous sodium carbonate solution. Ethyl chlorocarbonate (5.5 ml., 0.055 mole) is added dropwise over -20 minutes. The mixture is stirred at room temperature for 4 hr., the layers are separated, and the organic layer is dried over solid sodium carbonate. The ether is removed and the residual oil is crystallized from ethanol-water to give 14 g. of solid, M.P. 6265 C. Recrystallization from the same solvent system gives p-(N-carbethoxyaminophenyl) phenylacetonitrile melting at 95-97 C.

This material in 150 ml. of tetrahydrofuran is reduced at 8095 C. in the presence of Raney nickel under 1000 p.s.i. of hydrogen. The catalyst is removed and the solvent is evaporated. The residue is dissolved in 35% aqueous acetic acid and extracted with ether. The aqueous phase is made basic and extracted with methylene chloride. The organic solutions are dried and evaporated to produce a clear oil. The oil is triturated with petroleum ether to give crystals which are recrystallized from benzene-petroleum ether. The yield of 2-(p-N-carbethoxyaminophenyl)- 2-phenylethylamine, melting at 96-985 C. was 6.5 g.

To a suspension of 3 g. (0.08 mole) of lithium aluminum hydride in 50 ml. of ether is added dropwise over 15-20 minutes, an ethereal solution of 4 g. (0.014 mole) of the N-carbethoxyamino compound. The resulting suspension is stirred under reflux overnight. After cooling, the excess reducing agent is decomposed by the sequential addition of 1 ml. of H O/g. of hydride, 1 ml. of 10% sodium hydroxide/ g. of hydride, and then 3 ml. of water/ g. of hydride. The mixture is stirred 1 hr. at room temperature and the granular precipitate is filtered and the filter cake washed with ether. The filtrates are concentrated to an oil which distills at l60-170 C. at 1 mm. of Hg. The pale yellow oily distillate is dissolved in ether and saturated with hydrogen chloride. The salt is filtered, washed with ethyl acetate, and recrystallized from methanol-ethyl acetate twice to give 2 g. of the dihydrochloride, M.P. 254256 C. dec.

EXAMPLE 6 Preparation of 2- (p-dimethylaminophenyl) -2-phen'ylethylarnine hemitartrate To a mixture of platinum black (prepared from 0.2 g. of PtO 5 ml. of concentrated hydrochloric acid, 9.7 g. of 37% aqueous formaldehyde, and 60 ml. of ethanol is added 12.5 g. (0.06 mole) of (p-aminophenyl) phenylacetonitrile. An additional 30 ml. of ethanol is added and the mixture is hydrogenated on a Parr apparatus under an initial hydrogen pressure of 45 p.s.i. About 5.5 p.s.i. of hydrogen is absorbed after 45-50 minutes of shaking. The reduction is halted, the catalyst is removed, and the deep red filtrate is concentrated. The residue is diluted with water, made alkaline, and extracted with benzene. The combined extracts are dried (Na CO and concentrated to an oil. To remove any primary and secondary amines present the oil is treated with 14 ml. of acetic acid, 12 ml. of acetic anhydride, and a trace of zinc dust, and refluxed for 30 minutes. The mixture is cooled and decanted from the zinc into a beaker containing ice water. The aqueous mixture is extracted with benzene, the combined benzene phases are washed with 10% sodium hydroxide until alkaline and then are extracted thoroughly with dilute hydrochloric acid. The acidic washes are thoroughly extracted with ether to produce a clear yellow aqueous phase. This aqueous phase is basified with 10% sodium hydroxide and the resulting solid extracted into methylene chloride. Removal of the solvent leaves a solid residue which is recrystallized from ethanol to give 5 .5 g. of crystalline (p-dimethylaminophenyl) phenylacetonitrile, M.P. IOU-102 C.

A 15 g. sample of the cyano tertiary amine is reduced in methanol containing ammonia at room temperature in the presence of Raney nickel at 1000 p.s.i. of hydrogen. The catalyst is removed and the solvent is distilled to give an oil which is dissolved in ether. The ether is washed with dilute hydrochloric acid, the acid washes are combined, made basic, and extracted with ether. The ether is dried and evaporated. The residue distills at C. at less than 1 mm. of Hg. The distillate crystallizes on standing and Weighs 9.5 g., M.P. 72'74 C. A portion is converted to the tartrate salt, M.P. 241 C. dec. (CH OH).

EXAMPLE 7 Preparation of 2-(4-amino-3-tolyl)-2-phenylethylamine dihydrochloride 4-oxo 3 methyl-a-phenyl 2,5 cyclohexadiene-A', a-acetonitrile oxime [38 g., for preparation see R. B. Davis, L. C. Pizzini, and E. l. Bara, J. Org. Chem., 26, 4270 (1961)] is converted to (4-amino-3-tolyl) phenylacetonitrile with zinc amalgam as described in Example 2. The product weighs 35.7 g. and melts at 102-105 C.

Acetylation, as described in Example 3, produces a 76% yield of (4-aeetamido-3-tolyl) phenylacetonitrile, M.P.130131.5 C.

Reduction of this acetyl compound with Raney nickel under the conditions described in Example 2 gives 2-(4- acetamido-B-tolyl)-2-phenylethylamine as an oil.

The above amide is hydrolyzed by refluxing in 10% sulfuric acid. After neutralization and extraction the diamine is converted to the dihydrochloride, M.P. 280 281.5 C. after recrystallization from methanolethyl acetate.

EXAMPLE 8 Preparation of 2-(4-amino-3,5-xylyl)-2-phenylethylamine hemifumarate Twenty-seven g. of 3,5-dimethyl 4 oxo-a-phenyl-2, S-cyclohexadiene-A, a-acetonitrile oxime (prepared as described by Davis, Pizzini and Bara, loc. cit.) is reduced with zinc amalgam to the aminonitrile as in Example 2, M.P. 1141l6 C.

High pressure hydrogenation with Raney nickel catalyst gives the diamine which is distilled at -190 C.

at 1 mm. Hg and then converted to the hemifumarate. After recrystallization from methanol-ether the salt melted at 204205 C.

EXAMPLE 9 Preparation of 2- (p-aminophenyl -2- a-naphthyl) ethylamine 4-oxo-a-(1-naphthyl-2,5-cyclohexadiene-A, a acetonitrile oxime [R. B. Davis, L. C. Pizzini, and J. D. Benigni, J. Am. Chem. Soc., 82, 2913 (1960)] is reduced as described in Example 2 to give solid diamine as the free base, M.P. 17 8-179 C. after recrystallization from methanol.

EXAMPLE 10 Preparation of 2-(p-benzylaminophenyl)ant-phenylethylamine dihydrochloride A mixture of 31.2 g. (0.15 mol) of (p-aminophenyl; phenylacetonitrile 15.9 g. (0.15 mole) of benzaldehyde, and 250 ml. of methanol is stirred under reflux for 45 minutes. Cooling produces crystalline (p-N-benzylideneaminophenyl) phenylacetonitrile weighing 41.5 and melting at 120122 C.

A solution of 20 g. of the above Schiff base in 1 liter of methanol is treated twice with g. portions of sodium borohydride and stirred two hours at room temperature. After 45 minutes a clear solution results. The solution is diluted with several volumes of water and extracted with methylene chloride. The organic phases are com-- bined, dried (Na CO and evaporated to yield an oil which crystallizes when triturated with methanol. The aminonitrile is recrystallized from methanol to give 70% of product, M.P. 94-95 C.

Catalytic reduction, as in Example 2, gives the crude diamine which distills at 1 mm. of Hg at 210-220 C. Conversion to the dihydrochloride gives solid, M.P. 212- 215 C. dec. after recrystallization from methanol-ethyl acetate.

EXAMPLE 11 Preparation of 2,3-bis-naphthylpropylamine In a manner completely analogous to that described in Example 26, equimolar quantities of a-naphthaldehyde and a-naphthylacetonitrile are condensed to produce 2,3- bis-naphthylacrylonitrile.

Reduction gives the desired amine.

EXAMPLE 12 Preparation of 2-phenyl-2- (4-pyridyl) ethylamine hemifumarate To a cooled, stirred solution of 0.5 mole of 4-chloro pyridine and 0.5 mole of phenylacetonitrile in 200 ml. of dry toluene, is slowly added 40 g. of sodamide. A dense precipitate forms. The mixture is carefully diluted with water and the phases are separated. The organic phase is washed throughly with dilute hydrochloric acid and the combined acid extracts are extracted with toluene. The aqueous acid layer is made basic with 40% sodium hydroxide and the aqueous mixture is extracted with ethyl acetate. The ethyl acetate extracts are dried and evaporated. The residue is distilled in vacuo to produce a crystalline distillate which is recrystallized from ethyl acetate (yield 24 g.) M.P. 7678 C.

Reduction with Raney nickel, as in Example 2, gives an oil which distills in vacuo at 138-143 C. at 0.5 mm. of Hg. Conversion to the hemifumarate gives crystals which are recrystallized from methanol-ether, M.P. 178- 181 C.

EXAMPLE 13 Preparation of 2-(2-pyridyl)-2-(4-pyridyl) ethylamine hemifumarate In the manner exemplified above, 2-pyridylacetonitrile and 4-chloropyridine are allowed to react. The product is hydrogenated to give the dipyridyl ethylamine.

8 EXAMPLE 14 Preparation of 2-(3-methyl-4-pyridyl)-2-pyridylethylamine hemifumarate 2-pyridylacetonitrile [N. Sperber, et al., J. Am. Chem. Soc. 73, 5752 (1951)] and 4-bromo-3-picoline-N-oxide [L Itai and H. Ogura, Chem. Abstr., 50, 1809a (1956)] are used to prepare the dipyridyl acetonitrile.

High pressure hydrogenation reduced both the N-oxide and the nitrile to the desired amino compound which is isolated and purified as the hemifumarate.

EXAMPLE 15 Preparation of 2-(p-acetylphenyl) -3-phenylpropylamine hydrochloride ot-(4'-acetylphenyl) cinnamonitrile [K. Rorig, J. Am. Chem. Soc., 75, 5381 (1953)] is converted to the ethylene ketal with ethylene glycol and p-toluene-sulfonic acid in benzene. Hydrogenation of the ketal as described in Example 2, gives the ethylene ketal of 2-(p-acetylphenyl) 3-phenylpropylamine. This is converted to the keto compound with aqueous acetic acid. Neutralization gives the free base which is then converted to the hydrochloride.

EXAMPLE 16 Preparation of 2-phenyl-2-(p-tolyl) ethylamine hydrochloride (p-Tolyl) phenylacetonitrile [D. Shapiro, J. Org. Chem. 14, 839 (1949)] is reduced as described in Example 25. The crude amine is dissolved in ether and saturated with hydrogen chloride. The salt is filtered and recrystallized from acetone-ether, M.P. 232-234 C.

EXAMPLE 17 Preparation of 2-(p-hydroxypheny1)-2-phenylethylamine hydrochloride A mixture of 2.5 g. (0.01 mole) of Z-(p-methoxyphenyl)-2-phenylethylamine hydrochloride [H. B. Hass, M. B. Neher, and R. J. Blickenstaflf, Ind. Eng. Chem., 43, 2875 (1951)] 12.5 ml. of hydroiodic acid, and 12.5 ml. of acetic acid is refluxed for 6 hours. The solution is diluted with ice water, basified with 10% sodium hydroxide and extracted with ether. The ether is dried and saturated with hydrogen chloride to produce 500 mg. of product, M.P. 220-221 C. after purification from 1- butanol-ether.

' EXAMPLE 18 Preparation of 2- (p-mercaptophenyl -2-pheny1ethylamine hydrochloride Using the procedure described by T. Kappe and M. D. Armstrong, J. Org. Chem., 29, 826 (1964), 0.09 mole of thiophenol and 0.08 mole of 2-amino-1-phenylethanol are converted to the mercaptoamine. The hydrochloride is purified by recrystallization from ethanol-ether.

EXAMPLE 19 Preparation of 2-(p-methylthiophenyl)-2-pheny1- ethylamine hydrochloride EXAMPLE 20 Preparation of 2-(p-methylsulfinylphenyl) -2-phenylethylamine hydrochloride 3-(p-methylthiophenyl)-3-phenylpropionic acid from the previous example, is oxidized with an equimolar quantity of peracetic acid in excess acetic acid. The crude 3-(p-methylsulfinylphenyl)-3-phenylpropionic acid is isolated by diluting the acetic acid solution with several volumes of water. The sulfoxide is filtered, washed with water and dried.

The dry sulfoxide is subjected to the conditions of the Curtius reaction as in the previous example, and the amine sulfoxide is isolated and purified as the hydrochloride.

EXAMPLE 21 Preparation of '2- (p-methylsulfonylphenyl -2-phenylethylamine hydrochloride 3-(p-methylsulfonylphenyl)-3-phenylpropionic acid is prepared from the corresponding p-methylthio acid (Example 19) by oxidation with excess peracetic acid. The sulfone acid is converted to the amine as in Example 19. The HCl salt has a M.P. of 2l2214 C. after recrystallization from methanol-ether.

EXAMPLE 22 Preparation of 2,2-bis- (p-tolyl) -ethylamine hydrochloride A solution of 16.2 g. of bis-(p-tolyl) acetonitrile [R. F. Brown and N. M. van Gulick, I. Am. Chem. Soc., 77, 1083 (1955)] is hydrogenated as in Example 2. The hydrochloride of the resulting amine is recrystallized from a-propanol-ether, M.P. 245246 C.

EXAMPLE 23 Preparation of 2- (p-ethylaminophenyl -2-phenylethylamine hemifumarate (p-Aminophenyl) phenylacetonitrile (0.1 molesee Example is converted to (p-acetamidophenyl) phenylacetonitrile, M.P. 8688 C. with acetic anhydride. This amidon'itrile (0.08 mole) is hydrogenated, as in Example 2, to give 2-(p-acetamidophenyl)-2-phenylethy1amine as an oil.

To a stirred suspension of 6.5 (0.17 mole) of lithium aluminum hydride in 100 ml. of dry ether is added dropwise 8.8 g. (0.034 mole) of the aniidoamine prepared above in a mixture of ether and tetrahydrofuran (1:3 by volume). An additional 150 m1. of tetrahydrofuran is added and the mixture is refluxed for 3 hrs. and left at room temperature for 48 hrs. The excess lithium aluminum hydride is decomposed as in Example 5 and the product is isolated as an oil. The oil is distilled at l90-200 C. at less than 1 mm. of Hg and weighs 5.3 g. Conversion to the hemifumarate gives a solid which, after recrystallization from methanol-ether, melted at 177 178 C.

EXAMPLE 24 Preparation of 2-(p-n-butylaminophenyl)- 2-phenylethylamine hemifumarate (p n Butyrylaminophenyl) phenylacetonitrile, M.P. 112-113 C. is prepared in the manner shown in Example 23 and converted to 2-(p-n-butylaminophenyl)-2-phenylethylamine, as exemplified in that example. The hemifumarate recrystallizes from methanol-ether melted at 178-18l C.

EXAMPLE 25 Preparation of 3-phenyl-3-(p-trifluorornethylphenyl) propylamine hydrochloride 3-phenyl 3 (p-trifluoromethylphenyl) propionic acid (0.033) (prepared by the method described in Example 19) in 25 m1. of thionyl chloride is refluxed on a steam bath overnight. The excess thionyl chloride is removed in vacuo and the residual crude acid chloride is converted to the amide with cold aqueous ammonia. After cooling, the aqueous mixture is extracted with ether, the ether is washed with water, dried, and evaporated to an orange oil. The oil is recrystallized and recrystallized from benzene-petroleum ether, M.P. 9193 C.

Reduction of the amide, as described in Example 23, gives the propylamine as an oil. The hydrochloride recrystallizes from ethyl acetate-petroleum ether melted at 19ll92 C.

EXAMPLE 26 Preparation of 3-(p-dimethylaminophenyl)- 2-phenylpropylamine Seven g. of potassium hydroxide is dissolved in 50 ml. of methanol; to this solution 25 g. (.25 mole) of phenylacetonitrile is added. This solution is then added to a solution of 25 g. (.167 mole) of p-dimethylaminobenzaldehyde in 75 ml. of methanol. This mixture is heated to 50 C. for approximately one hour and then allowed to sit at room temperature. A yellow-green precipitate, 3-(p-dimethylaminophenyl)-2-phenyl I acrylonitrile, M.P. 134-137 C., is obtained in 93.47% yield.

Thirty-nine g. (.15 mole) of this intermediate, along with 400 ml. of methanol, 60 ml. of liquid ammonia, and 4 tsp. of Raney nickel are placed in a hydrogenation bomb. The starting pressure is 2130 p.s.i., and the maximum temperature reached is C. A yellow oil, 3-(pdimethylaminophenyl)-2-phenylpropylamine, is obtained from the reaction and, is converted to the dihydrochloride, M.P. 23l-233 C., in 73.33% yield.

EXAMPLE 27 Preparation of 3-(p-dimethylaminophenyD- Z-(p-methoxyphenyl)-propylamine In like manner to Example 26, 25 g. (.167 mole) of p-dimethylaminobenzaldehyde is condensed with 25 g. (.17 mole) of p-methoxyphenylacetonitrile, using potassium hydroxide as a catalyst, the only difference is that the mixture was heated to 50 C. for 6 hrs. A yellowgreen precipitate, 3-(p-dimethylaminophenyl)-2-(p-methoxyphenyl) acrylonitrile, M.P. 149151 C., is obtained in 75.40% yield.

In similar manner to the reduction above, 15 g. (.0541 mole) of this intermediate, along with ml. of methanol, 10 ml. of liquid ammonia, and 1 tsp. of Raney nickel are sealed in the hydrogenation bomb. The starting pressure is 2200 p.s.i., and the maximum temperature reached is 100 C. A white solid, 3-(p-dimethylaminophenyl)-2- (p-methoxyphenyl) propylamine is obtained from the reaction, in 92.97% yield, M.P. 7274 C.

EXAMPLE 28 Preparation of 3-(n-aminophenyl)- 2-phenylpropylamine Thirty-four g. (.226 mole) of m-nitrobenzaldehyde is poured into a solution of 23 g. (.197 mole) of phenylacetonitrile in 600 ml. of methanol; this is followed by the addition of 10 ml. of diethylamine. The reaction mixture is kept between 4050 C. for one hour, and then allowed to stand at room temperature. A silver-green precipitate, 3-(m-nitrophenyl)-2-phenyl acrylonitrile, is obtained in 96% yield.

Ten g. (.039 mole) of this intermediate, along with 140 ml. of methanol, 10 m1. of liquid ammonia, and two tsp. of Raney nickel are sealed in the hydrogenation bomb. The starting pressure is 2500 p.s.i., and the maximum temperature reached is 100 C. A bluish-green oil, 3-(maminophenyl)-2-phenylpropylamine, is obtained, and is then converted to the dihydrochloride.

1. 1 EXAMPLE 29 Preparation of 2-(p-aminophenyl)-3- p-methoxyphenyl propylamine In simliar manner to the above, 27.23 g. (.2 mole) of p-anisaldehyde is added to a solution of 37.29 g. (.23 mole) of p-nitrophenylacetonitrile, followed by the addition of ml. of diethylamine. The reaction mixture is kept beween 40-50 C. for one-half hour, and then allowed to stand at room temperature. A yellow precipitate, 3-(p-methoxyphenyl) 2 (p-nitrophenyl) acrylonitrile, M.P. 162l63 C. is obtained in approximately 100% yield.

In the manner described above, a hydrogenation step is carried out on g. (.0537 mole) of this intermediate. A brown solid, 2-(p-aminophenyl)-3-(p-rnethoxyphenyl) propylamine, is obtained from this reaction in 84.92% yield, M.P. 109111 C.

EXAMPLE 30 Preparation of 2- (p-aminophenyl)- Z-phenylpropylamine A mixture of 104 g. (0.5 mole) of (p-aminophenyl) phenylacetonitrile and 74 g. (0.5 mole) of phthalic anhydride in 2.5 liters of toluene is stirred and refluxed for hrs. in such a manner that the water formed during the reaction is removed by azeotropic distillation. The solution is cooled and the precipitated product is filtered. Concentration of the filtrate produces a second crop of product. The combined crops are recrystallized from dimethylformamide-water to give 153.6 g. of purified material [(p-phthalimidophenyl) phenylacetonitrile (1)], M.P. 22l222 C. The analytical sample melted at 224- 225 C.

A suspension of 13.52 g. (0.04 mole) of I above, and 2 g. of a mineral oil dispersion of sodium hydride (53% sodium hydride by weight) in 125 ml. of dry dimethylformamide is stirred at room temperature for a few minutes. To the resulting dark brown solution is added, fairly rapidly, 8 ml. of methyl iodide in ml. of dry dimethylformamide. The temperature rises to 40 45 C., and the brown color of the solution is discharged. The solution is stirred an additional 15 min. without external heating, and then for 20 min. on a steam bath. A pale yellow solution is diluted with several volumes of ice-water where upon a yellow gum separates. The gum is allowed to settle and the supernatant liquid is decanted. Trituration of the gum with ethanol yields white crystals. These are filtered and recrystallized from ethanol to give 8.9 g. of product, [2-phenyl-2-(p-phthalimidophenyl) propionitrile (IIa)] M.P. 148l49 C.

A mixture of 12.1 g. (0.034 mole) of 11a above, 200 ml. of ethanol and 12 ml. of 85% hydrazine is stirred and heated to reflux. Solution is effected after a short period of refluxing, followed almost immediately by the formation of a dense precipitate. Enough water is added to dissolve the precipitate, and stirring and refluxing are continued for 1 hr. The solution is stirred an additional hour at room temperature and diluted with water. The alcohol is removed and the aqueous residue is extracted with ether. The ether extracts are washed with Water until neutral and dried. Removal of the solvent leaves an oil which could be converted to a crystalline hydrochloride of Z-(p-aminophenyl)-2-phenylpropionitrile (II-Ia), M.P. 204206 C. dec. (n-butanol-hexane).

Crude IlIa above (about 8 g.), is reduced for 4 hrs. at 70 C. at 1000 p.s.i. of hydrogen in methanol, in the presence of Raney nickel and ammonia. The catalyst is removed and the methanolic filtrate is evaporated. The residue is dissolved in ethyl acetate, and filtered from a small amount of insoluble material. The filtrate is treated with gaseous hydrogen chloride to precipitate the dihydrochloride salt of the desired product, [2-(p-aminophenyl)- 2-phenylpropylamine dihydrochloride] which was recrys- 12 tallized from methanol-ethyl acetate, M.P. 278-280 C. dec., yield 52%, based on compound IIa.

EXAMPLE 31 Preparation of Z-(p-aminophenyl)-2-phenylhexylamine The n-butyl analog of the compound of Example 30 is prepared in an analogous manner thereto, with substitution of butyl iodide for methyl iodide. The hydrochloride salt of the hexylnitrile melts at 190193 C. (ethyl acetate). The dihydrochloride salt of the desired product has an M.P. of 272273 C. dec. (ethanol-ether).

EXAMPLE 32 Preparation of 2-(p-aminophenyl)-2,3-diphenylpr0pylamine hemihydrate The benzyl analog of the compound of Example 30 is prepared in a similar manner thereto, with substitution of benzyl halide for methyl iodide. The hydrochloride salt of the triphenylnitrile melts at 167168 C. The dihydrochloride salt of the desired product has an M.P. of 339- 340 C. dec. (methanol-ethyl acetate).

EXAMPLE 33 Preparation of 2- (p-aminophenyl -2-cyclohexylethylamine Para nitrophenylacetonitrile is reduced by zinc, amalgam and acetic acid. The product, p-aminophenylacetonitrile, is acetylated with acetic anhydride in acetic acid to produce the p-acetamidophenylacetonitrile, as outlined in Example 22.

Twenty g. of p-acetamidophenylacetonitrile is condensed with 30 g. of cyclohexanone in a solution composed of 40 g. of potassium hydroxide in 200 m1. of methanol at room temperature. The product, u-cyclohexylidene-p-acetamidophenyl-acetonitrile, is a light tan solid, M.P. 149-152 C.

Twelve g. of the above, a-cyclohexylidene-p-acetamidophenylacetonitrile, in 140' ml. of tetrahydrofuran is catalytically reduced over Raney nickel. The initial hydrogen pressure is 2000 lbs. and the maximum temperature reached during the reaction is C. The resulting product is hydrolyzed in concentrated hydrochloric acid and the product, 2-(p-aminophenyl)-2-cyclohexyl ethylamine, is isolated as the dihydrochloride salt, M.P. 292294 C. dec.

EXAMPLE 34 Preparation of 2-cyclohexyl-2-(p-methoxyphenyl) ethylamine One hundred and forty-seven g. of p-methoxy phenylacetonitrile is condensed with 100 g. of cyclohexanone in a solution composed of 65 g. of potassium hydroxide in 500 ml. of methanol. The resulting solution is refluxed for 1 hr. The product, tx-cyclohexyldiene-panethoxyphenylacetonitrile, is a white solid, M.P. 54-56 C.

Fifteen g. of the above intermediate, a-cyclohexylidenep-methoxyphenylacetonitrile, in ml. of methanol is catalytically reduced over Raney nickel. The initial hydrogen pressure is 1450 lbs. and the maximum temperature reached during the reaction is 100 C. The product is isolated as the hydrochloride salt, M.P. 231233 C. dec.

EXAMPLE 35 Preparation of 2-(p-chlorophenyl) -2-cyclohexylethylamine One hundred and fifty-two g. of p-chlorophenylacetonitrile is condensed with 100 g. of cyclohexanone in a solution composed of 65 g. of potassium hydroxide in 500 ml. of methanol. The resulting solution is refluxed for 45 minutes. The product, a-cyclohexylidene-p-chlorophenylacetonitrile, is a 'white solid, M.P. 42-45 C.

Fifteen g. of the above intermediate, a-cyclohexylidenep-chlorophenylacetonitri1e, in 135 ml. of tetrahydrofuran is catalytically reduced over Raney nickel. The initial hydrogen pressure is 1500 lbs. and the maximum temperature reached during the reaction is 70 C. The product is isolated as the hydrochloride salt, M.P. 274-277 C. dec.

The sucrose, calcium sulfate and d-2-(p-aminophenyl)- 2-phenylethyla'mine hydrochloride are thoroughly mixed and granulated with hot gelatin solution. The wetted mass is passed through a #6 mesh screen directly onto drying trays. The granules are dried at 120 F. and passed through a #20 mesh screen, mixed with the starch, talc and stearic acid, passed through a #60 mesh, and compressed into tablets. One tablet is administered two to twelve times a day.

EXAMPLE 37 Preparation of 3,3-diphenylpropylamine hydrochloride A mixture of 23 g. (0.1 mole) of diphenylpropionic acid and 48 g. (0.4 mole) of thionyl chloride is refluxed for 2 hrs. The excess thiouyl chloride is removed and the residue is evaporated again with benzene. The residue is dissolved in a small volume of benzene and added with stirring to 100 ml. of concentrated aqueous ammonia. The precipitated 3,3-diphenylpropionamide is cooled, filtered, washed with water, and recrystallized from ethanol to give 78% of product M.P. 125-127 C.

A solution of 14 g. (0.06 mole) of the above amide in 100 ml. of dry tetrahydroturan is added dropwise to a stirred suspension of 11.7 g. (0.31 mole) of lithium aluminum hydride in 200 ml. of dry ether. The mixture is refluxed for 6 hrs. after the addition is completed, and then is stirred overnight at room temperature. The complex is decomposed by the sequential addition of 11.7 ml. of water, 11.7 ml. of 10% sodium hydroxide, and ml. of water followed by stirring for 45 min. The granular precipitate is filtered and the filter cake is resuspended in either, stirred, and refiltered. The combined filtrates are dried (Na SO and evaporated. The residual oil weighs 13 g. It is dissolved in ether and saturated with hydrogen chloride to precipitate the hydrochloride. The salt is recrystallized from ethanolether to give 15.5 g. (60/) of the pure salt, M.P. 217- 218 C.

EXAMPLE 38 A preparation of 4,4-diphenylbutylamine hydrochloride Ingredients: Amounts (mg) 2-(p aminophenyl) 2 phenylethylamine hydrochloride Lactose 14 The above ingredients are screened through a #40 mesh screen, mixed well and filled into a #1 hard gelatin capsule. One capsule is administered two to twelve times daily.

EXAMPLE 40 Ingredients: Amounts (mg) 2 (p aminophenyl) 2 phenylethylamine hydrochloride 100.00 Magnesium stearate 5 .00 Lactose 400.00

The above ingredients are screened through a #40 mesh screen, mixed well and filled into a #0 hard gelatin capsule. One capsule is administered two to twelve times a day.

EXAMPLE 41 Ingredients: Amounts (mg) I 2-(3' methoxy 4 aminophenyl)-Z-phenylethylamine 25.00 Calcium sulfate dihydrate 125.00 Sucrose 25.00 Starch 15.00 Talc 5.00 Stearic acid 3.00

The sucrose, calcium sulfate and 2-(3-methoxy-4- aminophenyl)-2-phenylethylamine are thoroughly mixed and granulated with hot 10% gelatin solution. The wetted mass is passed through a #6 mesh screen directly onto drying trays. The granules are dried at F. and passed through a #20 mesh screen. These granules are then mixed with the starch, talc and stearic acid, passed through a #60 mesh screen and compressed into tablets.

EXAMPLE 42 Ingredients: Amounts (mg) 2-(p-aminophenyl)-2-phenylethylamine 150.00 Peanut oil 200.00

The ingredients are mixed to a thick slurry and filled into a soft gelatin capsule. One capsule is administered two to twelve times a day.

Also highly useful forms are sustained time release compositions which provide a substantially uniform dosage over an extended period of time, thus permitting reduction of the number of unit doses to be taken daily.

EXAMPLE 43 The sucrose, calcium sulfate and 2-(p-aminophenyl)- 2-phenylethylamine hydrochloride are thoroughly mixed and granulated with hot 10% gelatin solution. The wetted mass is passed through a #6 mesh screen directly onto drying trays. The granules are dried at 120 F. and passed through a #20 mesh screen, mixed with the starch, talc and stearic acid, passed through a #60 mesh, and compressed into tablets. One tablet is administered two to twelve times a day.

I claim:

1. The method of producing anti-adrenal activity which comprises internally administering to an animal organism requiring suppression of adrenal glandular function a daily dosage regimen from about 0.05 g. to about 16 g. of a compound selected from the group consisting of a tree base and its nontoxic, pharmaceutically acceptable acid additon salt thereof, said free base having the NRR' in which:

A is an alkylene linkage of from 1 to 4 carbon atoms;

R is hydrogen or acetyl;

R is hydrogen;

R" is hydrogen or alkyl to 7 carbon atoms;

Z is in the para position and represents amino, alkylamino having up to 4 carbon atoms, dialkylamino having up to 8 carbon atoms, acetamido, methyl, chloro, trifluoromethyl, hydroxy, mercapto, methylthio, methylsulfinyl, methylsulfonyl, or hydrogen; and

Z is hydrogen or, when Z is methyl, Z is methyl in the para position.

2. The method of producing anti-adrenal activity which comprises internally administering to an animal organism requiring suppression of adrenal glandular function a daily dosage regimen from about 0.05 to about 16 g. of a compound selected from the group consisting of a free base and its nontoxic, pharmaceutically acceptable acid addition salt thereof, said free base having the formula according to claim 1 wherein R, R, R" and Z are hydrogen, Z is p-amino, and A is methylene.

3. The method of producing anti-aldosterone activity which comprises internally administering to an animal organism requiring suppression of adrenal glandular function a daily dosage regimen from about 0.05 to about 16 16 g. of a compound selected from the group consisting of a free base and its nontoxic, pharmaceutically acceptable acid addition salt thereof, said free base having the formula according to claim 1 wherein R, R and Z are hydrogen, R" is methyl, Z' is p-amino, and A is methylene.

4. The method of producing anti-adrenal activity which comprises internally administering to an animal organism requiring suppression of adrenal glandular function a daily dosage regimen from about 0.05 to about 16 g. of a compound selected from the group consisting of a free base and its nontoxic, pharmaceutically acceptable acid addition salt thereof, said free base having the formula according to claim 1 wherein R, R, R", Z and Z' are hydrogen, A is methylene.

References Cited UNITED STATES PATENTS 2,421,714 7/1947 Rieveschl 260-570 2,751,388 6/1956 Levy 260294.7 3,266,988 8/1966 Saunders l6765 3,274,248 9/ 1966 Harsanyi et al. 260570 FOREIGN PATENTS 708,771 5/1954 Great Britain.

ALBERT T. MEYERS, Primary Examiner S. J. FRIEDMAN, Assistant Examiner US. Cl. X.R. 424324 

